NO316804B1 - Pharmaceutical compositions comprising monoamine oxidase B inhibitors, process for their preparation and use of the same - Google Patents

Abstract

A fast dispersing solid pharmaceutical composition having a monoamine oxidase B inhibitor as the only active ingredient is disclosed for the treatment of Parkinson's disease. The composition is formulated to promote absorption through the buccal, sublingual, pharyngeal and/or esophageal mucous membranes, such that at least 5% of the active ingredient is absorbed in one minute, as determined by a buccal absorption test.

Description

This invention encompasses a pharmaceutical composition, the process for preparing such a composition, and the use of such a composition in the treatment of Parkinson's disease, the treatment of depression and the treatment and/or prophylaxis of Alzheimer's disease.

Selegiline ((-)-N,α-dimethyl-N-2-propynyl-phenethylamine) is known to be useful in the treatment of Parkinson's disease. The mechanism of action of selegiline has not been fully elucidated. However, selegiline is a potent irreversible inhibitor of monoamine oxidase, with greater affinity for the type B form of the enzyme. Monoamine oxidase is known to play an important role in the breakdown of biological amines such as dopamine, norepinephrine and 5-hydroxytryptamine (serotonin) in the brain. It is believed that the inhibition of monoamine oxidase type B (MAO-B) can lead to the strengthening of the effects of dopamine and phenylethylamine in the brain of patients with Parkinson's disease, and thus lead to improved control of movements (see Gaal and Hermez, Chapter 4 in "Inhibitors of Monoamine Oxidase B, Pharmacology and Clinical Use in Neurodegenerative Disorders" edited by I. Szelenyi, (1993), Birkhauser Verlag Basel, Switzerland, hereinafter referred to as Szelenyi.)

Selegiline is currently administered orally in the form of plain tablets designed to be swallowed whole or a measured amount of plain syrup indicated to be swallowed rapidly. Consequently, selegiline administered in this way is absorbed from the gastrointestinal tract, that is, the stomach, small intestine and proximal colon, to the liver's portal system and presented to the liver before it reaches the systemic circulation. The liver is known to be the main site of conversion of active selegiline into metabolites, some of which are undesirable. The first passage of absorbed selegiline through the liver results in an extensive metabolism of the drug and a significant part of the absorbed dose of intact selegiline never reaches the systemic circulation and thus the brain. This phenomenon is known as "the first pass effect" and results in a decrease in the bioavailability of selegiline administered in this way (see Heinonen et al, Clinical Pharmacology & Therapeutics, Vol. 56, No. 6

(1994), pp. 742-749).

It is further known that selegiline is metabolized to the formation of N-desmethyl-selegiline, methamphetamine and amphetamine in accordance with the following metabolic pathway:

Although it has been suggested that N-desmethylselegiline may contribute to the desired inhibition of monoamine oxidase (see Heinonen et al (1993) in chapter 10 of Szelenyi), methamphetamine and amphetamine show no beneficial effect on Parkinson's disease. Since methamphetamine and amphetamine are both stimulants of the central nervous system and of the heart, their presence produces unwanted side effects such as insomnia and cardiac arrhythmias. To reduce the central nervous stimulating effect, currently available dosage forms of selegiline must be administered no later than mid-day, so that the unwanted stimulating effect has subsided before the patient wants to sleep at the end of the day. This situation is of course far from satisfactory.

Para-fluoroselegiline is an analogue of selegiline which is also a monoamine oxidase B inhibitor and shows very similar pharmacological activity to selegiline.

Many other compounds, often chemically unrelated to selegiline, also have monoamine oxidase B inhibitory properties, and several of these have also been shown to be useful in the treatment of Parkinson's disease, the treatment of depression and/or the prophylaxis of Alzheimer's disease . Among such MAO-B inhibitors can be mentioned: lazabemide {N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrogen chloride}; rasagiline {2,3-dihydro-N-2-propynyl-1H-inden-1-amine}; 2BUMP {N-(2-butyl)-N-methylpropargylamine; M-2-PP {N-methyl-N-(2-pentyl)-propargylamine}; MDL-72145 {beta-(fluoromethylene)-3,4-dimethoxy-bezenethanamine}; and mofegiline {(E)-4-fluoro-p-(fluoromethylene) benzene butanamine hydrogen chloride}.

WO 9001928 deals with the treatment of schizophrenia with 1-deprenyl (selegiline). Syrups containing the active ingredient (see claim 2), with 5-20 mg as the preferred dosage (claim 7), are described here as possible forms of administration.

EP 252290 B describes pharmaceutical compositions, including sublingual and buccal tablets (see pp. 2,1..47, pp. 3,1.5-13), containing levodopa methyl ester in combination with MAO-B inhibitors, for the treatment of Parkinson's disease.

EP 436492 describes the preparation and pharmaceutical preparations of N-propargyl-1-aminoindan, an MAO-B inhibitor. Among other things, the possibility of producing syrups and sublingual tablets is mentioned here (see pp. 5, 1.11 and examples 15-17).

It emerges from Schneider, L.S. et al., Clin. Pharmacol. Ther. 56, 750-6

(1994), that the MAO-B inhibitor selegiline is known to treat depression, Parkinson's disease and Alzheimer's disease (see abstract).

Although it will be obvious to a person skilled in the field that an administration route of MAO-B inhibitors, and especially selegiline, which bypasses hepatic first-pass metabolism, there is nothing that makes it obvious for a person skilled in the art to choose a technical solution of the type described in the present patent claims.

From a clinical point of view, it is highly desirable to find a way to administer such MAO-B inhibitors, so that the bioavailability of the active ingredient is enhanced and thus monoamine oxidase inhibition has a faster onset and extended duration.

In accordance with the present invention, a pharmaceutical mixture for oral administration has therefore been provided, comprising a carrier and as active ingredient, a monoamine oxidase B inhibitor characterized in that the composition is formulated to promote pre-gastric absorption of the active ingredient.

The term "pre-gastric absorption" is used to refer to the absorption of the active ingredient from the part of the digestive tract before the stomach and includes oral cavity, tongue, larynx and esophagus absorption.

The potential for pre-gastric absorption of compositions containing MAO-B inhibitors can be determined using the method described for selegiline in Example 3 below. This test is similar to the "oral absorption test" which is said by Harris and Robinson in a review article (J.. Pharm. Sei., 1992, vol 81, p 1-10) to be a well-recognized method for evaluating oral absorption of medicines.

The test formulation containing the clinically effective dose of MAO-B inhibitors is thus held in the mouth for 1 minute before being spit out. The mouth is then cleaned with 3 aliquots of 25 ml of water which are spit out in the same way. The total amount of MAO-B inhibitor is determined in the saliva using an appropriate analytical technique such as HPLC, and the remaining amount of MAO-B inhibitor is subtracted from the total amount of drug initially placed in the mouth to thereby determine the total amount of the drug that has been absorbed pre-gastrically. In order for a significant absorption to have occurred, it is generally preferred that at least 5% of the MAO-B inhibitor has been absorbed in 1 minute in this test, and preferably that at least 10% has been absorbed in 1 minute and most preferably that at least 15% of MAO-B inhibitor has been absorbed in 1 minute.

It is expected that such pre-gastric absorption will occur primarily via the mucous membrane of the mouth, pharynx and esophagus. It is therefore preferred that the invented mixture is formulated to accelerate the absorption of the active ingredient through the mucous membrane of the oral cavity, under the tongue, throat and/or esophagus.

It is therefore preferred that the invented mixture should be in a form which maintains the active ingredient in contact with the oral cavity, tongue, pharynx and/or the mucous membrane of the esophagus.

Preferably, that the invented mixture is in the form of a viscous emulsion, syrup or elixir, a tablet under the tongue, a lozenge or chewable tablet, softgel, lozenge, aqueous or non-aqueous drops or other dosage forms designed to release the active ingredient on a controlled way to saliva or to the mucous membranes of the oral cavity, pharynx and/or esophagus, a fast-dispersing dosage form designed to rapidly release the active ingredient in the oral cavity, or a bioadherent system.

The term "bioadherent system" refers to a solid or liquid dose which, at body temperature, shows controlled release and the characteristics of the bioadherent. This type of dosage form can be an emulsion which is water in oil, whose internal phase is larger than the external phase. An example of such a bioadherent system can be found in the U.S. Patent No. 5,055,303.

Clinical studies have shown that up to 82% of patients with Parkinson's disease have difficulty swallowing and that many such patients tend to drool.

Accordingly, of the dosage forms listed above, fast dispersing dosage forms are particularly preferred because they will dissolve quickly in the mouth and thus minimize the above problem. It is therefore expected that such rapidly dispersing dosage forms will be easier for patients to take and easier for carers to administer.

An example of a rapidly dispersing dosage form is described in U.S. Pat.

Patent No. 4 855 326 where an auxiliary substance, such as sugar is combined with the active ingredient and the mixture is spun into a "sugar-spun" preparation. The spun "sugar-spun" product is then compressed into a rapidly dispersing, highly porous solid dosage form.

U.S. Patent No. 5,120,549 discloses a rapidly dispersing matrix system which is made by first solidifying a matrix-forming system dispersed in the first solvent and then in contact with a solidified matrix in the second solvent, which is substantially miscible with the first solvent at a temperature lower than the freezing point of the first solvent. Matrix formed substances and active ingredient become substantially insoluble in the second solvent, whereby the first solvent is substantially removed and results in a rapidly dispersing matrix.

U.S. Patent No. 5,079,018 discloses a rapidly dispersing dosage form comprising a porous skeletal structure of a water-soluble hydrated gel or foam-forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent, and dehydrated with an organic solvent at a temperature around 0°C or lower to make room for the hydration fluid.

Published International Application No. WO 93/12769 (PCT/JP93/01631) describes rapidly dispersing dosage forms of very low density formed by gelation with agar, aqueous systems containing matrix-forming elements and active ingredients and subsequent removal of water by compressed air or vacuum drying.

U.S. Patent No. 5,298,261 describes rapidly dispersing dosage forms which include a partially degraded matrix network which has been vacuum dried above the degradation temperature of the matrix. The matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.

Published International Application No. WO 91/04757 (PCT/US90/05206) describes rapidly dispersing dosage forms containing an effervescent disintegrant designed to effervesce in the presence of saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.

The term "quickly dispersing dosage form" therefore includes all types of dosage forms described in the preceding section. It is particularly preferred that the fast-dispersing dosage form is of the type described in UK patent no. 1548022, that is, solid fast-dispersing dosage form comprising a network of active ingredients and a water-soluble or water-dispersing excipient which is inert in relation to the active ingredient. The network has been obtained by sublimating the solvent from the mixture in solid form, that mixture containing the active ingredient and a solution of the excipient in a solvent.

It is preferred that the invented mixture decomposes within 1 to 10 seconds, preferably 2 to 8 seconds after being placed in the oral cavity.

In the case of the preferred type of rapidly dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or plant proteins, such as gelatin, dextrin and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/proteins or polysaccharide complexes such as gelatin-acacia complexes.

Other matrix-forming substances for use in the present invention include sugar forms such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugar such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

One or more matrix-forming agents may be incorporated into the solution or suspension prior to solidification. The matrix-forming agent may be presented in addition to a surfactant or to the exclusion of a surfactant. In addition to forming a matrix, the matrix forming agent can assist in maintaining the dispersion of any active ingredient within the solution or suspension. This is particularly useful in the case of active agents which are not sufficiently soluble in water and therefore must be suspended rather than dissolved.

Secondary components such as preservatives, antioxidants, surfactants, viscosifiers, dyes, flavorings, sweeteners or flavor masking agents may also be incorporated into the mixture. Suitable dyes include red, black and yellow iron oxides and FD&C colors such as FD&C Blue No. 2 and FD & C red No. 40 available from Bilis & Everad. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, sherry and grape flavors and combinations thereof. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and malic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable flavor masking agents include sodium bicarbonate, ion exchange resins, cyclodextran compounds, adsorbates or microencapsulated active ingredients.

According to a first aspect of the present invention, a pharmaceutical composition for oral administration is covered containing an excipient and as active ingredient, a monoamine oxidase B inhibitor selected from the group consisting of mofegiline, lazabemide and compounds of the general formula:

where X represents a hydrogen atom or a methyl group and Y represents a fluorine or hydrogen atom, and pharmaceutically acceptable salts of said monoamine oxidase B inhibitor, characterized in that the mixture is in the form of a solid fast-dispersing dosage form containing a network of active ingredients and a water-soluble or a water-dispersing excipient which is inert in relation to the active ingredient, the network having been formed by sublimation of the solvent from the mixture in solid form, the mixture containing the active ingredient and a solution of the excipient in a solvent.

Preferred compositions in accordance with this invention include as the active MAO-B inhibitor a compound of general formula:

or an acid addition salt, where X represents a hydrogen atom or, preferably, a methyl group and Y represents fluorine or, preferably, a hydrogen atom. It is particularly preferred that X is methyl and Y is hydrogen, i.e. that the active MAO-B inhibitor is selegiline.

Selegiline or para-fluoroselegiline which has been absorbed by pre-gastric absorption from a mixture in accordance with this invention passes directly into systemic circulation thus avoiding first-pass metabolism in the liver.

Consequently, the initial rapid production of unwanted metabolites is reduced and the bioavailability of active selegiline or para-fluoroselegiline is increased. This

resulting in a number of benefits. For example, the increased bioavailability of active selegiline or para-fluoroselegiline means that the dose of selegiline or para-fluoroselegiline can be reduced but still produce the desired beneficial effect. This will result in a further reduction in the production of unwanted metabolites and in the case of selegiline a corresponding reduction in the stimulating effect of methamphetamine and amphetamine on the central nervous system and heart. Accordingly, no restrictions on dosing time are required for the inventive composition.

In the case of selegiline and its analogues of formula I above, the active ingredient is preferably present in the composition in an amount of 1 to 30%, and more preferably 1 to 20% by weight of the composition. It is also preferred that the active ingredient is present in the mixture in an amount from 0.25 to 30 mg, preferably 0.5 to 10 mg and most preferably 1 to 5 mg.

In the case of other MAO-B inhibitors, these will also be present in concentrations that are clinically effective.

In accordance with another aspect of the invention, a method for the preparation of a pharmaceutical mixture as defined above has been provided which consists of bringing an auxiliary substance into association with the MAO-B inhibiting active ingredient.

The invention also provides, seen in a wider perspective, a mixture as defined above for use in the treatment of Parkinson's disease.

As mentioned above, selegiline and para-fluoroselegiline are both inhibitors of monoamine oxidase B. The preferred substrate for monoamine oxidase B is phenethylethylamine, a chemical that occurs naturally in the brain. Phenethylethylamine is structurally very closely related to amphetamine and new studies indicate that phenylethylamine can act as a neuromodulator and promote increased mood. This is a result of the fact that patients suffering from depression have been shown to have sub-normal levels of phenylethylamine in the brain.

In light of this, it has been suggested that monoamine oxidase B inhibitors such as selegiline may be useful in the treatment of depression because inhibition of monoamine oxidase B will result in increased levels of phenylethylamine. However, in practice, it has generally been found that high doses, typically 30-60 mg per day for long periods (eg 6 weeks) of selegiline are required to increase mood in depressed patients. Such high doses are associated with non-specific inhibition of both monoamine oxidase A and monoamine oxidase B. Selective inhibition of monoamine oxidase B is a feature of low doses (10 mg or less) of selegiline. Although monoamine oxidase A has very little effect on the metabolism of phenylethylamine, it has been suggested that inhibition of monoamine oxidase A may produce an anti-depressant effect by inhibiting the deamination of norepinephrine and 5-hydroxytryptamine (serotonin), whose deficiency is also associated with depression. But inhibition of monoamine oxidase A can produce unwanted cardiovascular effects and tyramine-induced hypertensive crisis (the so-called "cheese effect") Consequently, the use of such high doses of selegiline or other MAO-B inhibitors to combat depression is clearly far from ideal.

As an alternative, it has been suggested to give a low dose of selegiline (10mg) in conjunction with phenylalanine (250mg), which is a precursor of phenylethyleneamine. In this combination, selegiline inhibits the production of monoamine oxidase B and thereby inhibits the deamination of phenylethylamine and phenylalanine stimulates phenylethylamine synthesis. This results in an increased level of phenylethylamine in the brain, which therefore contributes to an increased mood. But two agents are needed and given and the onset of the antidepressant effect is still slow.

To date, no studies have demonstrated consistent antidepressant efficacy using low doses of selegiline alone. But it has now been discovered that if selegiline or, by mixing other MAO-B inhibitory compounds formulated in accordance with the present invention, an increase in the amount of phenylethylamine can occur in the body and thus a good antidepressant effect can be achieved at dose levels associated with selective inhibition of mono-oxidase B. Furthermore, it is likely that an earlier onset of effect is achieved than with existing formulations and in the case of selegiline, the low dose level results in low levels of unwanted metabolites and therefore a reduction in their associated side effects.

In accordance with other aspects of the invention, there is therefore provided the use of a mixture as defined above for the preparation of a drug for the treatment and/or prophylaxis of depression.

Recent studies have also shown that selegiline and other MAO-B inhibitors have a positive effect in the treatment and/or prophylaxis of Alzheimer's disease because this condition is also associated with a marked increase in the levels of monoamine oxidase B in the brain when compared to age-matched controls. Because the formulation of selegiline and other MAO-B inhibitors in a mixture in accordance with the present invention has been shown to increase the bioavailability of active ingredients, such a mixture may be particularly effective in the treatment and/or prophylaxis of Alzheimer's disease while minimizing unwanted metabolites and associated side effects.

In accordance with other aspects of the invention, the composition as defined above for the preparation of a medicament for the treatment and/or prophylaxis of Alzheimer's disease is provided.

Since it is well known that demented patients with Alzheimer's disease may not comply with the treatment regimen, and may be uncooperative and even spit out the tablets, the rapidly dispersing dosage forms of the invention are particularly preferred, not only will they disintegrate quickly in the mouth and thus reduce the possibility of ejection of the entire dosage form, but it has been shown that a significant part of the active ingredient is absorbed into the body from this dosage form even if a part is spit out.

The invention is further illustrated by the following example.

EXAMPLE 1

Preparation of a fast dispersing dosage form of selegiline

(a) Preparation of selegiline hydrochloride 2.0% dispersion

Gelatin (720 g) and mannitol (540 g) were dispersed in a portion of purified water (15.73 kg) by thorough mixing in a bowl of a vacuum mixer. The rest of the water (1.5 litres) was added under vacuum while mixing with an anchor stirrer. The mixture was then heated to 40°C ± 2°C and homogenized for ten minutes. The mixture was cooled to room temperature. Once cooled, a 4500 g portion of the mixture was transferred to a stainless steel container and glycine (360 g), aspartame (90 g), grapefruit flavoring (54 g), opatin yellow (54 g), citric acid (90 g) and selegiline hydrochloride ( 360 g) was added to this portion while it was being homogenized using a bench homogenizer. The remaining part of the mixture was transferred to another stainless container. The mixture was homogenized for 10 minutes using a bench mixer to dissolve the drug. When the dispersion of the dye was finished, the homogenized portion in the first container was mixed together with the mixture from the second container. The mixture was then mixed for at least 20 minutes. The main dispersion was then homogenized to ensure complete mixing.

(b) Preparation of 5 mg units of selegiline hydrochloride

250 mg of selegiline hydrochloride 2.0% dispersion formed in (a) above was dosed into a series of ready-made bladder pockets with a pocket diameter of 12 mm. Bladder laminate consisting of PVC/30 nm PE/PVDC 90 g per square meters. The product was frozen immediately in a liquid nitrogen freezing tank. The frozen product was then stored below -20°C for a minimum of 24 hours before freeze drying in a freeze dryer with a drying temperature of +20°C and a chamber pressure of 0.5 mbar. The freeze-dried units were then inspected for critical defects and the remaining package sealed with foil consisting of a paper/foil laminate (20 µm aluminum). Each bladder was then coded with a batch number and packaged in a pre-made bag by placing the bladder in the bag and sealing the open end of the bag completely. Each bag was then coded with product name, batch number, date of manufacture and supplier's name.

Each dose unit had the following mixture:

EXAMPLE 2

Comparative pharmacokinetics study

The purpose of this experiment was to compare the bioavailability of the selegiline hydrochloride formulation in Example 1 with the commercially available tablet formulation of selegiline hydrochloride sold under the registered trademark "Movergan" by Astra Medica AG, Weismullerstrasse 45, 600 Frankfurt am Main, Germany.

An unlabeled ("open label"), randomized, 2-way crossover, voluntary study was conducted as follows. Twenty-four individuals of both sexes, aged between 45 and 71 years, gave written informed consent and underwent a thorough medical examination to determine their fitness to participate in the study. Subjects received the study treatment in the order dictated by a predetermined randomized list. The subjects were either given the formulation in Example 1 or the "Movergan" formulation. Blood samples for determination of pharmacokinetic parameters were taken at baseline (just before administration of the drug), then 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6 , 8,10,12, 24,48, 72 and 96 hours. Study procedures were repeated two weeks later, when subjects were crossed over to receive their second drug allocation. Selegiline hydrochloride was dispensed as a single 10mg dose (made from 2 x 5mg tablets) of the formulation in Example 1 or of the "Movergan" formulation.

Analyzes were performed to determine the concentration of selegiline, N-desmethyl-selegiline, methamphetamine and amphetamine in each of the blood plasma samples. The following pharmacokinetic parameters were determined for all four analyzed substances: bioavailability (measured as area under the curve (AUC) of drug concentrations/time) Cmax (maximum plasma concentration achieved and Tmax (time when Cmax was observed).

The results are shown graphically in Figures 1 to 4 where each figure is a representation of the concentration of a specific component in a blood plasma sample against the time when the sample was taken for the formulation in Example 1 (Example 1) and the tablet formulation sold under the registered trademark "Movergan" (Mover organ). In Figure 1, the specific component is selegiline. In Figure 2, the specific component is N-desmethyl-selegiline. In Figure 3, the specific component is methamphetamine. In Figure 4, the specific component is amphetamine.

The results are shown in numerical form in table 1 below. In this table, the references to N-desmethylselegiline, methamphetamine and amphetamine are L-(-)- isomers of these components.

From Figures 1 to 4 and Table 1, it is clear that the bioavailability of selegiline from the formulation in Example 1 is more than 8 times higher than selegiline from the "Movergan" formulation despite the fact that both formulations contain the same amount of active ingredient. The bioavailability of N-desmethylselegiline is also very similar for both formulations. The bioavailability of methamphetamine and amphetamine, which are known not to contribute to the therapeutic effect, is very similar for Example 1 and the "Movergan" formulation. In light of the much greater bioavailability of selegiline from the formulation in Example 1, it is desirable that the dose of selegiline could be significantly reduced by significantly reducing the amount of unwanted central nervous and cardiac stimulating metabolites and unwanted side effects caused by these, while still achieving desired levels of selegiline in plasma and thus the desired therapeutic effect associated with mono-oxidase B inhibition.

In table 1, ratio of the area under the plasma concentration-time curve (AUK) for

selegiline and AUC for N-desmethylselegiline was 0.0233 for the "Movergan" formulation, clearly indicating the extensive metabolism of selegiline when administered in the existing dosage form. The corresponding AUK ratio for example 1 in table 1 was 0.1894. It demonstrates that pre-gastric absorption of selegiline results in a greater proportion of the given dose being absorbed in unmetabolised form. The

further demonstrates that the selegiline : N-desmethylselegiline AUK ratio can be used as another indicator of the degree of pre-gastric absorption in selegiline-containing compositions in accordance with the invention. It is generally preferred that the ratio of selegiline AUK to N-desmethyl-selegiline AUK should be greater than 0.05 and preferably greater than 0.075 and most preferably greater than 0.10.

EXAMPLE 3

Pre-gastric absorption study

The purpose of this study was to determine the sublingual absorption of the selegiline hydrochloride formulations produced in relation to Example 1. Pharmacokinetic profile of selegiline hydrochloride from the commercially available US tablet formulation sold under the registered trademark "Eldepryl" by Somerset Pharmaceuticals Inc. 777 South Harbor Island Boulevard, Suit 880, Tamp, Florida 33602, served as a control for the degree of gastro-intestinal absorption of selegiline. In addition, a study was designed to compare urinary excretion over 24 hours of phenylethylamine and 5-hydroxyindole-acetic acid (5-HIAA) from individuals to whom such formulations have been administered.

This study was an unlabelled, randomized 3-way crossover voluntary study and was conducted as follows: Eleven individuals of both sexes aged between 45 and 62 years gave written informed consent and underwent a thorough medical examination to determine their fitness to participate in the study. The subjects each received the following treatments in an order dictated by a predetermined randomized list.

1) 2 x 5 mg Eldepryl tablets taken with 150 ml of water

(Eldepryl (10 mg))

2) 2 x 5 mg selegiline tablets prepared in accordance with Example 1 held in the mouth for 1 minute and then spit out and the mouth cleaned with 3 x 25 ml water and then spit out (Example 1 (2.96 mg)) 3) 2 x 5 mg selegiline tablets prepared in accordance with Example 1 held in the mouth i

1 minute and then swallowed ( example 1 (10 mg)).

Blood samples for determination of pharmacokinetic parameters were taken at baseline (just before the drug was administered) and then 0.08, 0.16, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4 , 6 and 12 hours. Urine samples were taken immediately before the drug was given and during the periods 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 12-24 hours.

Analyzes were performed to determine the concentration of selegiline in each of the blood plasma and urine samples and the concentration of phenylethylamine and 5-hydroxyindole acetic acid (5HIAA) were measured in each of the urine samples. Selegiline was also measured in saliva and in mouthwash.

Phenylethylamine is the preferred substrate for monoamine oxidase B (MAO-B) and consequently its excretion has been shown to increase when MAO-B is inhibited. 5HIAA is a breakdown product formed by the action of MAO-A on 5-hydroxytryptamine seretonin). When MAO-A is inhibited, the secreted level of 5HIAA has been shown to decrease.

The results of the study are shown graphically in Figures 5, 6, and 7. When the tablets made in accordance with Example 1 were held in the mouth for 1 minute and spit out, an average concentration equivalent to 7.04 mg of selegiline hydrochloride was measured orally - the rinsing water. Consequently, an average of 2.96 mg of selegiline hydrochloride was absorbed pre-gastrically with this treatment. Subjects therefore received 2.96 mg or 10 mg of selegiline hydrochloride from the 10 mg formulation made in accordance with claim 1 and 10 mg of selegiline from the Eldepryl formulation. Figure 5 is a plot of concentrations of selegiline in foal plasma samples versus time of sample collection for both spit out and swallowed formulations made in accordance with Example 1 (Example 1 (equivalent to 2.96 mg) and Example 1 (10 mg)) and 10 respectively mg tablet formulation sold under the registered trademark "Eldepryl". Figure 6 shows cumulative 5-hydroxyindodecacetic acid excretion in urine over 24 hours. Figure 7 shows cumulative phenylethylamine excretion in urine over 24 hours.

From Figure 5, it is clear that the bioavailability of selegiline from both the 2.96 mg (spit out) equivalent and 10 mg (swallowed) doses made in accordance with Example 1 is much greater than that of selegiline from the "Eldepryl" formulation despite for the fact that a formulation (Example 1 (10 mg "swallowed")) contains the same amount of active ingredient as the "Eldepryr formulation and spit out treatment contains less than a third of the amount of active ingredient as the "Eldepryr formulation. Furthermore, it is clear from Figure 7 that this increase in bioavailability is associated with a dose related increase in urinary excretion of phenylethylamine. This was an unexpected result since increased phenylethylamine excretion is caused by inhibition of monoamine oxidase B and it was previously thought that 10 mg of selegiline in standard tablet form (eg "Eldepryl") would be sufficient to cause maximal inhibition of monoamine oxidase B during the first 24 hours. In addition, the higher rate of excretion of phenylethylamine in Figure 7 for Example 1 (10 mg "swallowed") and Example 1 (2.96 mg "spit out") than for the "Eldepryr formulation" indicates a faster rate of monoamine oxidase B inhibition than with previous mixtures, and thus a possible earlier relief of symptoms of Parkinson's disease, Alzheimer's disease and depression than for the "Eldepryr formulation.

Lack of inhibition of monoamine oxidase A by Example 1 (10 mg "swallowed") and Example 1 (2.96 mg "spit out") treatments was strengthened by analysis of urine samples for concentration of 5-hydroxyindoleacetic acid, which is the metabolite of 5 -hydroxytryptamine (serotonin) which is the main substrate for monoamine oxidase A (see Figure 6). Urine concentrations of 5-hydroxyindo-acetic acid were similar for Example 1 (10 mg "swallowed"), Example 1 (2.96 mg "spit out") and standard "Eldepryf tablet formulations, showing that the selegiline formulations made in accordance with Example 1 did not cause greater MAO-A inhibition than standard tablets despite greatly increased selegiline bioavailability.

Once again, in light of the greater bioavailability of selegiline from Example 1 (2.96 mg "spit out") formulations it is assumed that the dose of selegiline can be significantly reduced d thus significantly reducing the amount of unwanted metabolites with associated side effects while still achieves the desirable therapeutic effects associated with inhibition of monoamine oxidase B.

The following examples further exemplify the formulations that can be made using the process described in Example 1 that will promote pre-gastric absorption of selegiline and other MAO-B inhibitors:

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6 EXAMPLE 7

EXAMPLE 8 EXAMPLE 9

EXAMPLE 10

EXAMPLE 11

Claims (17)

1. Pharmaceutical mixture for oral administration containing an excipient and as active ingredient, a monoamine oxidase B inhibitor selected from the group consisting of mofegiline, lazabemide and compounds of the general formula: where X represents a hydrogen atom or a methyl group and Y represents a fluorine or hydrogen atom, and pharmaceutically acceptable salts of said monoamine oxidase B inhibitor, characterized in that the mixture is in the form of a solid fast-dispersing dosage form containing a network of active ingredients and a water-soluble or a water-dispersing excipient which is inert in relation to the active ingredient, the network having been formed by sublimation of the solvent from the mixture in solid form, the mixture containing the active ingredient and a solution of the excipient in a solvent. 2. Mixture according to claim 1, characterized in that the mixture is formulated to promote absorption of the above-mentioned monoamine oxidase B inhibitor through the oral cavity, sublingual, esophagus and/or esophageal mucosa. 3. Bandage according to claims 1 and 2, characterized in that the mixture is formulated so that at least 5%, preferably at least 10%, and most preferably at least 15% of said monoamine oxidase B inhibitor is absorbed for one minute in oral cavity absorption. 4. Mixture according to claim 1, characterized in that X represents a methyl group and Y represents a hydrogen atom. 5. Mixture according to claim 4, characterized in that the active ingredient is present in an amount from 1 to 30% of the weight of the mixture 6. Mixture according to claim 4, characterized in that the active ingredient is present in an amount from 0.25 to 30 mg. 7. Mixture according to claim 4, characterized in that the mixture is formulated so that the ratio of the area under the plasma concentration-time curve for selegiline to that for N-desmethylselegiline is greater than 0.05, preferably greater than 0.075 and most preferably greater than 0.10. 8. Pharmaceutical mixture for oral administration containing an excipient and as active ingredient, a monoamine oxidase B inhibitor according to any of the preceding claims, characterized in that the mixture is in the form of a viscous emulsion, syrup or elixir, sublingual tablets, a suction or chewable tablet, mold, drops, aqueous or non-aqueous drops or other dosage forms designed to release the active ingredient in a controlled manner into saliva or to the oral cavity, throat and/or oesophageal mucosa, a rapidly dispersing dosage form designed to rapidly release the active ingredient in the oral cavity, or a bioadherent system, formulated to promote pre-gastric absorption of the above monoamine oxidase B inhibitor. 9. Mixture according to claim 8, characterized in that the mixture disintegrates within 1 to 10 seconds after being placed in the oral cavity. 10. Pharmaceutical mixture for oral administration according to claim 1, characterized in that the monoamine oxidase B inhibitor is selegiline. 11. Pharmaceutical composition for oral administration according to claim 10, characterized in that it comprises selegiline in a dosage form which disintegrates within 1 to 10 seconds after being placed in the oral cavity. 12. Mixture as defined in any of the preceding claims, characterized for use in the treatment of Parkinson's disease. 13. Use of the mixture as defined in any of claims 1 to 11, for the production of a drug for the treatment and or prophylaxis of depression. 14. Use of a mixture as defined in any one of claims 1 to 11, for the production of a drug for the treatment and/or prophylaxis of Alzheimer's disease. 15. Use of a composition as defined in any of claims 1 to 11 for the manufacture of a medicament for raising the levels of phenylethylamine in the body. 16. Use of a composition as defined in any one of claims 1 to 11, for the manufacture of a medicament for the treatment of diseases associated with sub-normal levels of phenylethylamine. 17. Method for producing a pharmaceutical mixture in accordance with each of the preceding claims, characterized in that it includes bringing a carrier into contact with the above-mentioned active ingredient.